Chen Liang, Pan Jingxuan
Jinan University Institute of Tumor Pharmacology, College of Pharmacy, Jinan University, Guangzhou, China.
Br J Pharmacol. 2017 Aug;174(15):2427-2443. doi: 10.1111/bph.13836. Epub 2017 Jun 18.
Aberrant activation of the cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6)-Rb signalling pathway is common in oesophageal squamous cell carcinoma (ESCC). PD-0332991, a highly specific inhibitor of CDK4/6, has potent antitumour activity against many types of cancer. The purpose of this study was to examine the in vitro and in vivo antineoplastic effect of PD-0332991 against the growth and metastasis of ESCC cells.
Cell viability and any synergy between PD-0332991 and 5-fluorouracil or cisplatin were measured by MTS assay and CalcuSyn software respectively. Cell migration and invasion were detected by wound healing and transwell assays. Apoptosis was evaluated by flow cytometry after staining annexin V-FITC/PI. Cellular senescence was assessed by measuring SA-β-gal activity. Nude mouse xenograft models of ESCC were employed to determine the in vivo activity of PD-0332991 against tumour growth and lung metastasis.
PD-0332991 inhibited cellular growth and induced mitochondrial-dependent apoptosis in ESCC cells. PD-0332991 also suppressed migration, invasion and the expression of MMP-2 in ESCC cells. Furthermore, PD-0332991 treatment caused cell senescence in a FOXM1-dependent manner. In addition, there was synergy between PD-0332991 and cisplatin or 5-fluorouracil. Importantly, the xenografted tumour experiments demonstrated that PD-0332991 potently inhibits ESCC cell growth and lung metastasis.
PD-0332991 can elicit a strong antitumour activity against ESCC growth and metastasis and may be a promising candidate drug for the treatment of patients with ESCC. Our results warrant a clinical trial to further evaluate the efficacy of PD-0332991 in ESCC patients, even those with metastasis.
细胞周期蛋白D1-细胞周期蛋白依赖性激酶4/6（CDK4/6）-Rb信号通路的异常激活在食管鳞状细胞癌（ESCC）中很常见。PD-0332991是一种高度特异性的CDK4/6抑制剂，对多种癌症具有强大的抗肿瘤活性。本研究的目的是检测PD-0332991对ESCC细胞生长和转移的体外及体内抗肿瘤作用。
分别通过MTS法和CalcuSyn软件检测细胞活力以及PD-0332991与5-氟尿嘧啶或顺铂之间的协同作用。通过伤口愈合实验和Transwell实验检测细胞迁移和侵袭能力。用膜联蛋白V-FITC/PI染色后通过流式细胞术评估细胞凋亡。通过检测SA-β-半乳糖苷酶活性评估细胞衰老。采用ESCC裸鼠异种移植模型确定PD-0332991对肿瘤生长和肺转移的体内活性。
PD-0332991抑制ESCC细胞的生长并诱导其发生线粒体依赖性凋亡。PD-0332991还抑制ESCC细胞的迁移、侵袭以及MMP-2的表达。此外，PD-0332991处理以FOXM1依赖的方式导致细胞衰老。此外，PD-0332991与顺铂或5-氟尿嘧啶之间存在协同作用。重要的是，异种移植肿瘤实验表明，PD-0332991能有效抑制ESCC细胞生长和肺转移。
PD-0332991对ESCC的生长和转移具有强大的抗肿瘤活性，可能是治疗ESCC患者的一种有前景的候选药物。我们的结果值得进行临床试验，以进一步评估PD-0332991对ESCC患者（甚至是有转移的患者）的疗效。
